Novel inflammatory markers associated with cognitive performance: Singapore Longitudinal Ageing Studies Qi Gao a , Xavier Camous b , Yan-Xia Lu b , May-Li Lim a , Anis Larbi b, 1 , Tze-Pin Ng a, * ,1 a Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore b Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A * STAR), Singapore article info Article history: Received 20 July 2015 Received in revised form 8 December 2015 Accepted 9 December 2015 Available online 15 December 2015 Keywords: Inflammation Cognition Aging sgp130 sIL-2Ra sTNFR2 abstract We identified and validated several novel inflammatory markers of cognitive performance in community-living older persons. An exploratory study (n ¼ 83) correlated 177 inflammatory markers assayed by Luminex with the MinieMental State Examination (MMSE) and identified 8 inflammatory markers for enzyme-linked immunosorbent assay (ELISA) and correlations with MMSE, Montreal Cognitive Assessment (MoCA), and cognitive impairment in the validation study (n ¼ 139). The validation study replicated the significant associations of soluble interleukin-2 receptor alpha chain (sIL-2Ra; p ¼ 0.050), soluble tumor necrosis factor receptor 2 (sTNFR2; p ¼ 0.002) and soluble glycoprotein 130 (sgp130; p ¼ 0.026) with MMSE, and sIL-2Ra (p ¼ 0.019) and sgp130 (p < 0.001) with MoCA. Significant trends of associations of tertiles of sgp130, sIL-2Ra, and sTNFR2 were found with cognitive impairment. Highly elevated estimates of association of high versus low tertiles were obtained for sgp130 (odds ratio [OR] ¼ 4.24, 95% confidence interval [CI] 0.96e18.8), sIL-2Ra (OR ¼ 3.94, 95% CI 0.83e18.7), and sTNFR2 (OR ¼ 7.58, 95% CI 1.19e48.1). sgp130, sTNFR2, and sIL-2Ra are promising inflammatory markers of low cognitive performance for further investigation. Ó 2016 Elsevier Inc. All rights reserved. 1. Introduction Against the backdrop of a dramatic increase of the world’s aged population, cognitive impairment, cognitive decline, and dementia in older persons have become a major public health priority in this century. In 2010, dementias were present worldwide in 5%e7% of the 60 þ population. The number of persons with dementia will double every 20 years (Prince et al., 2013) exacting high socioeco- nomic costs in all countries and overwhelming burden of care on families and caregivers. Dementia is a generic syndrome due to different pathologies including Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal dementia, and dementia with Lewy Bodies. Their common feature is a progressive loss of cognitive functions lead- ing to functional dependency and death. Growing evidence sug- gests that inflammation plays an important role in the pathogenesis of cognitive decline and dementia (Dziedzic, 2006). Experimental studies show that chronic inflammation is involved in the pathogenesis of various neurodegenerative diseases. In AD, the accumulation of misfolded amyloid causes massive inflam- mation in the brain mediated by the microglia and brain-resident immune cells (Combs et al., 2000). VaD caused by microinfarcts of cerebral blood vessels depriving oxygen supply to neurons is partly due to inflammation of the arterial wall leading to the accumulation of thrombotic factor (Libby et al., 2009). In dementia with Lewy bodies, the accumulation of fibrillary a-synuclein could trigger the activation of microglia cells to induce inflammatory response by producing proinflammatory cytokines such as inter- leukin (IL)-b (Codolo et al., 2013). Inflammation is an aggravating if not causative factor of these neurodegenerative brain diseases. Thus, for the most common dementias, an inflammatory compo- nent is commonly present in the evolution of distinct neuro- pathological processes that result in early detectable impairment of cognitive functions. It is of great interest and importance to know whether before the clinical manifestations of dementia, low cognitive function and cognitive impairment associated with developing neurode- generative pathologies in the brain leaves an inflammatory marker that is measurable and can be used as a predictive marker of predementia or early dementia. Clinical studies have * Corresponding author at: Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, 9th Floor, 1E Kent Ridge Road, 119228, Singapore. Tel.: þ65 67724514; fax: þ65 67772191. E-mail address: pcmngtp@nus.edu.sg (T.-P. Ng). 1 Both authors contribute equally. Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging 0197-4580/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.002 Neurobiology of Aging 39 (2016) 140e146